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Intracellular Activation Events for Parietal Cell Hydrochloric Acid Secretion

Catherine S. Chew

10.1002/cphy.cp060313

Source: Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion

Originally published: 1989

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Evidence Supporting A Role For Cyclic Amp in Control of Parietal Cell Hydrochloride Acid Secretion
2 Cyclic Amp‐Dependent and Cyclic Amp‐Independent Protein Kinases in Parietal Cells
3 Role Of Calcium in Control of Acid Secretion
4 Future Perspectives
Figure 1. Figure 1.

Effect of islet‐activating protein and pertussis toxin on PGE2 inhibition of histamine‐stimulated [14C]aminopyrine (AP) accumulation in rabbit gastric glands. Glands were preincubated 4 h at 37°C with 250 ng/ml pertussis toxin (hatched bars) or no additions (open bars), rinsed, then stimulated in the presence of [14C]aminopyrine for 45 min with 1 μM histamine ± 1 μM PGE2. [14C]aminopyrine accumulation was determined at the end of the 45‐min incubation period. Values are means ± SE for 5 experiments.

Data from Brown and Chew 22
Figure 2. Figure 2.

Time course of activation of cAMP‐dependent protein kinase and [14C]aminopyrine (AP) accumulation in response to histamine. Parietal cells from same preparations were preincubated for 30 min at 37°C and then stimulated with 10‐4 M histamine. Aliquots of cells were removed at indicated times for determination of [14C]aminopyrine uptake and cAMP‐dependent protein kinase activity. Values are means ± SE for 5 experiments. Lower lines in each group, basal values. *P < 0.01, significantly different from basal.

From Chew 28
Figure 3. Figure 3.

Time course of changes in parietal cell free intracellular Ca2+ ([Ca2+]i) in response to several agonists that elevate cAMP content, as compared with carbachol, which does not increase cAMP. Parietal cells 97% enriched) were loaded with 2 μM fura 2 AM, the membrane‐permeant acetomethylester form of the fluorescent Ca2+ indicator, fura 2, for 20 min at 37°C, rinsed, and then stimulated with agonists. Tracings of responses to different agonists were superimposed for direct comparisons. Left to right: carbachol 10‐4 M), histamine 10‐4 M), forskolin 10‐4 M), isobutylmethylxanthine 10‐4 M). Neither 8‐brcAMP 5 × 10‐4 M) nor Bt2cAMP 1 mM) had any detectable effect on the fura 2 signal (lower tracing).

From Chew and Brown 33
Figure 4. Figure 4.

Comparison of Ca2+‐dependent protein phosphorylation patterns in parietal and chief cells from rabbit gastric mucosa. Cells were enriched on Nycodenz gradients followed by centrifugal elutriation. Supernatants 50,000 g) of homogenates of each cell type were prepared and assayed for Ca2+‐dependent protein kinase activity. Phosphorylated proteins were identified with sodium dodecyl sulfate‐polyacrylamide electrophoresis (SDS‐PAGE) followed by autoradiography. Top: superimposed densitometric tracings of phosphorylated proteins from parietal cells 99% parietal). Bottom: chief cell (<5% parietal) protein phosphorylation. Darkened areas, increased phosphorylation due to Ca2+ addition. Autoradiographs of control (lower lane) and Ca2+‐treated (upper lane) homogenates are aligned with densitometric tracings for direct comparisons. Molecular weights (x103) are indicated at top of figure. Note differences in phosphorylation patterns in 2 cell types. (C. S. Chew and M. R. Brown, unpublished observations.)
Figure 5. Figure 5.

Model of neural, endocrine, paracrine control mechanisms in parietal cell HCl secretion. Histamine binds H2 receptors, causing release of α‐subunits from Gs, a GTP‐binding protein with stimulatory activity. Forskolin also causes release of α‐subunits from Gs. The α‐subunits activate adenylate cyclase and phospholipase C (P'lipase C). Result is increased cellular cAMP concentration and breakdown of phosphatidylinositol 1,4‐bisphosphate (PIP2) to form inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol (DAG). Cholera toxin elevates cAMP by NAD‐dependent ribosylation of Gs; prostaglandins inhibit histamine‐stimulated activation of adenylate cyclase by causing release of inhibitory α‐subunits from Gi, a GTP‐binding protein with inhibitory activity. Release of αi‐subunits is blocked by pertussis toxin‐induced NAD‐dependent ribosylation of Gi. Acetylcholine and gastrin activate phospholipase C and increase IP3 by activating other GTP‐dependent regulatory components (Go) that may also contain α‐subunits (αo). The αo‐subunits could also have actions independent of phospholipase C activation. Agonist‐induced increases in [Ca2+]i and cAMP lead to activation of Ca2+ and cAMP‐dependent protein kinases, which then phosphorylate a variety of intracellular proteins. Increased protein phosphorylation may lead to morphological transformation that precede HCl secretion and increased cellular metabolism that parallels acid secretory activity. Protein phosphorylation may directly or indirectly regulate the H+‐K+‐ATPase and/or other cellular transport processes.


Figure 1.

Effect of islet‐activating protein and pertussis toxin on PGE2 inhibition of histamine‐stimulated [14C]aminopyrine (AP) accumulation in rabbit gastric glands. Glands were preincubated 4 h at 37°C with 250 ng/ml pertussis toxin (hatched bars) or no additions (open bars), rinsed, then stimulated in the presence of [14C]aminopyrine for 45 min with 1 μM histamine ± 1 μM PGE2. [14C]aminopyrine accumulation was determined at the end of the 45‐min incubation period. Values are means ± SE for 5 experiments.

Data from Brown and Chew 22


Figure 2.

Time course of activation of cAMP‐dependent protein kinase and [14C]aminopyrine (AP) accumulation in response to histamine. Parietal cells from same preparations were preincubated for 30 min at 37°C and then stimulated with 10‐4 M histamine. Aliquots of cells were removed at indicated times for determination of [14C]aminopyrine uptake and cAMP‐dependent protein kinase activity. Values are means ± SE for 5 experiments. Lower lines in each group, basal values. *P < 0.01, significantly different from basal.

From Chew 28


Figure 3.

Time course of changes in parietal cell free intracellular Ca2+ ([Ca2+]i) in response to several agonists that elevate cAMP content, as compared with carbachol, which does not increase cAMP. Parietal cells 97% enriched) were loaded with 2 μM fura 2 AM, the membrane‐permeant acetomethylester form of the fluorescent Ca2+ indicator, fura 2, for 20 min at 37°C, rinsed, and then stimulated with agonists. Tracings of responses to different agonists were superimposed for direct comparisons. Left to right: carbachol 10‐4 M), histamine 10‐4 M), forskolin 10‐4 M), isobutylmethylxanthine 10‐4 M). Neither 8‐brcAMP 5 × 10‐4 M) nor Bt2cAMP 1 mM) had any detectable effect on the fura 2 signal (lower tracing).

From Chew and Brown 33


Figure 4.

Comparison of Ca2+‐dependent protein phosphorylation patterns in parietal and chief cells from rabbit gastric mucosa. Cells were enriched on Nycodenz gradients followed by centrifugal elutriation. Supernatants 50,000 g) of homogenates of each cell type were prepared and assayed for Ca2+‐dependent protein kinase activity. Phosphorylated proteins were identified with sodium dodecyl sulfate‐polyacrylamide electrophoresis (SDS‐PAGE) followed by autoradiography. Top: superimposed densitometric tracings of phosphorylated proteins from parietal cells 99% parietal). Bottom: chief cell (<5% parietal) protein phosphorylation. Darkened areas, increased phosphorylation due to Ca2+ addition. Autoradiographs of control (lower lane) and Ca2+‐treated (upper lane) homogenates are aligned with densitometric tracings for direct comparisons. Molecular weights (x103) are indicated at top of figure. Note differences in phosphorylation patterns in 2 cell types. (C. S. Chew and M. R. Brown, unpublished observations.)



Figure 5.

Model of neural, endocrine, paracrine control mechanisms in parietal cell HCl secretion. Histamine binds H2 receptors, causing release of α‐subunits from Gs, a GTP‐binding protein with stimulatory activity. Forskolin also causes release of α‐subunits from Gs. The α‐subunits activate adenylate cyclase and phospholipase C (P'lipase C). Result is increased cellular cAMP concentration and breakdown of phosphatidylinositol 1,4‐bisphosphate (PIP2) to form inositol 1,4,5‐trisphosphate (IP3) and diacylglycerol (DAG). Cholera toxin elevates cAMP by NAD‐dependent ribosylation of Gs; prostaglandins inhibit histamine‐stimulated activation of adenylate cyclase by causing release of inhibitory α‐subunits from Gi, a GTP‐binding protein with inhibitory activity. Release of αi‐subunits is blocked by pertussis toxin‐induced NAD‐dependent ribosylation of Gi. Acetylcholine and gastrin activate phospholipase C and increase IP3 by activating other GTP‐dependent regulatory components (Go) that may also contain α‐subunits (αo). The αo‐subunits could also have actions independent of phospholipase C activation. Agonist‐induced increases in [Ca2+]i and cAMP lead to activation of Ca2+ and cAMP‐dependent protein kinases, which then phosphorylate a variety of intracellular proteins. Increased protein phosphorylation may lead to morphological transformation that precede HCl secretion and increased cellular metabolism that parallels acid secretory activity. Protein phosphorylation may directly or indirectly regulate the H+‐K+‐ATPase and/or other cellular transport processes.

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Article Title: Intracellular Activation Events for Parietal Cell Hydrochloric Acid Secretion
 

How to Cite

Catherine S. Chew. Intracellular Activation Events for Parietal Cell Hydrochloric Acid Secretion. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 255-266. First published in print 1989. doi: 10.1002/cphy.cp060313